Though there has been a considerable amount of research in improving peripheral nerve guide design, commercially available nerve guides have not equaled the regenerative capacity of the nerve autograft in long gap peripheral nerve repair. While autografts (e.g., the sural nerve) have been used to bridge nerve defects of 6 cm or more (Kim et al., 2008, “Nerve Injuries: operative results from major nerve injuries, entrapments, and tumors. 2nd ed. Philadelphia: Saunders Elsevier. pp. 1-611), polymer based nerve guides are effectively used to regenerate nerves in gaps that span only 3 cm or less (Schlosshauer et al., 2006, Neurosurgery 59(4):740-748). This barrier in gap length may reflect the unmet need for nerve guides to actively promote nerve regeneration through the lumen of the guide from the proximal to the distal nerve stump (Kemp et al., 2008, Neurol. Res. 30:1030-1038).
In addition to providing mechanical support for regenerating nerves, nerve guides should also provide cues that guide axonal growth and increase the rate at which nerves regenerate.
The complex problem of targeting axonal outgrowth has led to the investigation of a variety of nerve guide materials, luminal fillers, cell therapies and combinations thereof (Midha et al., 2003, J. Neurosurg. 99(3):555-565). One additional pathway toward enhancing axonal growth involves locally delivering drugs or neurotrophic factors that promote nerve growth and survival. Growth factors have been delivered from nerve guides by adsorbing the growth factor to the nerve guide scaffold, incorporating growth factors into the scaffold material during fabrication (Chavez-Delgada et al., 2003, J. Biomed. Mater. Res. B. Appl. Biomater. 67B(2):702-711; Yang et al., 2005, J. Control Release 104(3):433-446), embedding growth factor loaded rods or microspheres into the nerve guide (Fine et al., 2002, Eur. J. Neurosci. 15(4):589-601; Bloch et al., 2001, Exp. Neurol. 172(2):425-432; Xu et al., 2003, Biomaterials 24(13):2405-2412; Rosner et al., 2003, Ann. Biomed. Eng. 31(11):1383-1401; Goraltchouk et al., 2006, J. Control Release 110(2):400-407; Singh et al., 2008, Tissue Eng Part C Methods 14(4):299-309; Dodla et al., 2008, Biomaterials 29(1):33-46), covalently immobilizing growth factors onto the nerve guide surface (Chen et al., 2006, J. Biomed. Mater. Res. A. 79A(4):846-857; Wood et al., 2009, J. Biomed. Mater Res A 89A(4):909-918; Lee et al., 2003, Exp. Neurol. 184(1):295-303), or by implantation of an osmotic pump (Newman et al., 1996, Arch Otolaryngol Head Neck Surg 122(4):399-403; Lewin et al., 1997, Laryngoscope 107(7):992-999) (for review of these techniques, see Kemp et al., 2008, Neurol. Res. 30:1030-1038 and Willerth et al., 2007, Adv. Drug Deliv. Rev. 59(4-5):325-338). Results from these preclinical studies have shown beneficial effects of delivered growth factors for nerve regeneration. For example, the delivery of nerve growth factor (NGF) promotes sensory neuron survival, outgrowth and branching (Bloch et al., 2001, Exp. Neurol. 172(2):425-432), ciliary neurotrophic factor (CNTF) aids in motor neuron survival and outgrowth (Xu et al., 2009, J. Clin. Neurosci. 16(6):812-817) and glial cell line-derived neurotrophic (GDNF) has been shown to promote the regeneration of fibers originating from the spinal cord beyond what has been measured with NGF (Fine et al., 2002, Eur. J. Neurosci. 15(4):589-601). Because of the promising reports following treatment of nerve injuries with neurotrophic factors, the delivery of such factors can be a potential method of surpassing the current length limitations in nerve regeneration. While strategies have been developed for protein delivery from polymer nerve guides, many conduit delivery systems lack a sustained and controlled release rate of bioactive proteins for the entire duration required for the axon to cross from the proximal to the distal nerve stump. Accordingly, there remains a need for nerve guides and other medical devices that can deliver an active agent for therapeutically effective periods.